# Genetic Modifiers of Retinal Disease

> **NIH NIH R01** · JACKSON LABORATORY · 2020 · $544,593

## Abstract

PROJECT SUMMARY/ABSTRACT
According to the 2014 National Health Survey, 22.5 million people in the US suffer from vision loss or
blindness from many causes, including heritable retinal disorders, for which effective treatments are generally
unavailable. CRB1 variants cause heritable retinal degenerative phenotypes ranging from Leber congenital
amaurosis, characterized by congenital or early-onset blindness, to retinitis pigmentosa, a more slowly
progressive disease. CRB1 RP variants are often associated with unique disease features, such as retinal
telangiectasia with or without exudative retinal detachment (Coat's disease), a loss of RPE pigmentation
except near arterioles (preservation of para-arteriolar RPE or PPRPE), pigment paravenous chorioretinal
atrophy, cone-rod dystrophy, nanophthalmos with optic disc drusen, and macular dystrophic disease. Limited
evidence for genotype-phenotype correlations in patients bearing CRB1 mutations has been detected. This
suggests that interactions of mutant CRB1 with either environmental factors or genetic modifiers are the likely
cause of the variability in disease phenotypes observed.
In this proposal, we will specifically address the genetic complexities underlying CRB1-associated disease.
Through a sensitized chemical mutagenesis screen, we have identified 12 novel mouse models bearing
epistatic genetic modifiers associated with the Crb1rd8 mutation. These models on defined genetic
backgrounds, raised in controlled environments will allow us to answer the following questions: 1) What are the
genetic modifiers that interact with Crb1rd8 to cause the clinical phenotypes observed including retinal
dysplasia, reduction in visual acuity and diminished electroretinographic response? 2) What cell types
contribute to the disease phenotypes? 3) What are the pathogenic mechanisms that are induced by the genetic
modifiers that lead to these phenotypes? 4) Can shared mechanisms be identified that might serve as a
blueprint for future therapeutic intervention to delay, prevent, or reverse the disease?
The goal of this proposal is to determine the molecular basis of the genetic modifiers and the pathogenic
mechanisms underlying the disease phenotypes to which they contribute. These studies address a critical
unmet need for developing effective therapies that can target the pre-symptomatic stage to prevent, delay
onset or decrease severity of the disease. Animal models serve an important and unique role to further our
understanding of the genetic underpinnings of disease and as a resource to examine tissue pathology, and to
perform pre-clinical therapeutic tests that cannot be readily conducted in humans.

## Key facts

- **NIH application ID:** 9967010
- **Project number:** 5R01EY027305-04
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** MARK P KREBS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $544,593
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967010

## Citation

> US National Institutes of Health, RePORTER application 9967010, Genetic Modifiers of Retinal Disease (5R01EY027305-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9967010. Licensed CC0.

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